WIN 55,212-2

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WIN 55,212-2
WIN 55,212-2-2D-skeletal.svg
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Identifiers
  • (11R)-2-Methyl-11-[(morpholin-4-yl)methyl]-3-(naphthalene-1-carbonyl)-9-oxa-1-azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene
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Chemical and physical data
Formula C27H26N2O3
Molar mass 426.516 g·mol−1
3D model (JSmol)
  • CC1=C(C2=C3N1[C@@H](COC3=CC=C2)CN4CCOCC4)C(=O)C5=CC=CC6=CC=CC=C65
  • InChI=1S/C27H26N2O3/c1-18-25(27(30)22-9-4-7-19-6-2-3-8-21(19)22)23-10-5-11-24-26(23)29(18)20(17-32-24)16-28-12-14-31-15-13-28/h2-11,20H,12-17H2,1H3/t20-/m1/s1 X mark.svgN
  • Key:HQVHOQAKMCMIIM-HXUWFJFHSA-N X mark.svgN
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Pancreatic stellate cells. The cells in the lower frame are under the action of WIN 55,212-2. They are thought to assume a more "quiescent" phenotype. From Michalski et al., 2008. Pancreatic stellate cell cropped.png
Pancreatic stellate cells. The cells in the lower frame are under the action of WIN 55,212-2. They are thought to assume a more "quiescent" phenotype. From Michalski et al., 2008.

WIN 55,212-2 is a chemical described as an aminoalkylindole derivative, which produces effects similar to those of cannabinoids such as tetrahydrocannabinol (THC) but has an entirely different chemical structure. [3] [4] [5]

Contents

WIN 55,212-2 is a potent cannabinoid receptor agonist [6] that has been found to be a potent analgesic [7] in a rat model of neuropathic pain. [8] It activates p42 and p44 MAP kinase via receptor-mediated signaling. [9]

At 5 μM WIN 55,212-2 inhibits ATP production in sperm in a CB1 receptor-dependent fashion. [10]

WIN 55,212-2, along with HU-210 and JWH-133, may prevent the inflammation caused by amyloid beta proteins involved in Alzheimer's disease, in addition to preventing cognitive impairment and loss of neuronal markers. This anti-inflammatory action is induced through agonist action at cannabinoid receptors, which prevents microglial activation that elicits the inflammation.

WIN 55,212-2 is a full agonist at the CB1 cannabinoid receptor (Ki  = 1.9 nM) and has much higher affinity than THC (Ki = 41 nM) for this receptor. [11] WIN 55,212-2 is also an agonist of the PPARα and PPARγ nuclear receptors. [12]

WIN 55,212-2 reduces voluntary wheel running in laboratory mice, but with effects that depend on both genetic background and sex. [13]

In the United States, all CB1 receptor agonists of the 3-(1-naphthoyl)indole class such as WIN 55,212-2 are Schedule I Controlled Substances. [14] WIN 55,212-2 is illegal in the UK. [15]

WIN 55,212-2 is also a CB2 receptor agonist and thereby, like other cannabinoid CB2 agonists, found to significantly improve cardiac recovery after ischaemia/reperfusion (I/R) in the hearts of diabetic fatty rats, by restoring coronary perfusion pressure and heart rate to pre-ischaemic levels, by the restoration of the inducible nitric oxide synthase (iNOS)/endothelial nitric oxide synthase (eNOS) cardiac equilibrium. [16] [17]

See also

Related Research Articles

<span class="mw-page-title-main">Cannabinoid</span> Compounds found in cannabis

Cannabinoids are several structural classes of compounds found in the cannabis plant primarily and most animal organisms or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoactive compound in cannabis. Cannabidiol (CBD) is also a major constituent of temperate cannabis plants and a minor constituent in tropical varieties. At least 113 distinct phytocannabinoids have been isolated from cannabis, although only four have been demonstrated to have a biogenetic origin. It was reported in 2020 that phytocannabinoids can be found in other plants such as rhododendron, licorice and liverwort, and earlier in Echinacea.

<span class="mw-page-title-main">Cannabinoid receptor</span> Group of receptors to cannabinoid compounds

Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system of vertebrates– a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains. Cannabinoid receptors are activated by three major groups of ligands: endocannabinoids; phytocannabinoids ; and synthetic cannabinoids. All endocannabinoids and phytocannabinoids are lipophilic.

<span class="mw-page-title-main">Cannabinol</span> Naturally-occurring cannabinoid

Cannabinol (CBN) is a mildly psychoactive cannabinoid that acts as a low affinity partial agonist at both CB1 and CB2 receptors. This activity at CB1 and CB2 receptors constitutes interaction of CBN with the endocannabinoid system (ECS).

<span class="mw-page-title-main">Tetrahydrocannabivarin</span> Homologue of tetrahydrocannabinol

Tetrahydrocannabivarin is a homologue of tetrahydrocannabinol (THC) having a propyl (3-carbon) side chain instead of pentyl (5-carbon), making it non-psychoactive. It has been shown to exhibit neuroprotective activity, appetite suppression, glycemic control and reduced side effects compared to THC, making it a potential treatment for management of obesity and diabetes.

<span class="mw-page-title-main">HU-210</span> Chemical compound

HU-210 is a synthetic cannabinoid that was first synthesized in 1988 from (1R,5S)-myrtenol by a group led by Raphael Mechoulam at the Hebrew University. HU-210 is 100 to 800 times more potent than natural THC from cannabis and has an extended duration of action. HU-210 has a binding affinity of 0.061nM at CB1 and 0.52nM at CB2 in cloned human cannabinoid receptors compared to Delta-9-THC of 40.7nM at CB1. HU-210 is the (–)-1,1-dimethylheptyl analog of 11-hydroxy- Δ8- tetrahydrocannabinol; in some references it is called 1,1-dimethylheptyl- 11-hydroxytetrahydrocannabinol. The abbreviation "HU" stands for Hebrew University.

<span class="mw-page-title-main">JWH-133</span> Chemical compound

JWH-133(Dimethylbutyl-deoxy-Delta-8-THC) is a potent selective CB2 receptor agonist with a Ki of 3.4nM and selectivity of around 200x for CB2 over CB1 receptors. It was discovered by and named after, John W. Huffman.

<span class="mw-page-title-main">Parahexyl</span> Chemical compound

Parahexyl is a synthetic homologue of THC which was invented in 1941 during attempts to elucidate the structure of Δ9-THC, one of the active components of cannabis.

<span class="mw-page-title-main">Ajulemic acid</span> Chemical compound

Ajulemic acid (1',1'-Dimethylheptyl-delta-8-tetrahydrocannabinol-11-oic acid) (DMH-D8-THC-11-OIC) (AB-III-56, HU-239, IP-751, CPL 7075, CT-3, JBT-101, Anabasum, Resunab, Lenabasum) is a synthetic cannabinoid that shows anti-fibrotic and anti-inflammatory effects in pre-clinical studies without causing a subjective "high". Although its design was inspired by a metabolite of delta-9-THC known as delta-9-THC-11-oic acid, ajulemic acid is an analog of the delta-8-THC metabolite delta-8-THC-11-oic acid. It is being developed for the treatment of inflammatory and fibrotic conditions such as systemic sclerosis, dermatomyositis and cystic fibrosis. It does not share the anti-emetic effects of some other cannabinoids, but may be useful for treating chronic inflammatory conditions where inflammation fails to resolve. Side effects include dry mouth, tiredness, and dizziness. The mechanism of action is through activation of the CB2 receptor leading to production of specialized proresolving eicosanoids such as lipoxin A4 and Prostaglandin J2. Studies in animals at doses up to 40 mg/kg show minimal psychoactivity of ajulemic acid, compared to that produced by tetrahydrocannabinol. A composition of ajulemic acid named Lenabasum (formerly Anabasum, Resunab) is being developed by Corbus Pharmaceuticals (formerly JB Therapeutics) for the treatment of orphan chronic life-threatening inflammatory diseases.

<span class="mw-page-title-main">NAGly receptor</span> Protein-coding gene in the species Homo sapiens

N-Arachidonyl glycine receptor, also known as G protein-coupled receptor 18 (GPR18), is a protein that in humans is encoded by the GPR18 gene. Along with the other previously "orphan" receptors GPR55 and GPR119, GPR18 has been found to be a receptor for endogenous lipid neurotransmitters, several of which also bind to cannabinoid receptors. It has been found to be involved in the regulation of intraocular pressure.

<span class="mw-page-title-main">GPR55</span> Protein-coding gene in the species Homo sapiens

G protein-coupled receptor 55 also known as GPR55 is a G protein-coupled receptor that in humans is encoded by the GPR55 gene.

<span class="mw-page-title-main">Cannabinoid receptor type 1</span> Mammalian protein found in Homo sapiens

Cannabinoid receptor type 1 (CB1), also known as cannabinoid receptor 1, is a G protein-coupled cannabinoid receptor that in humans is encoded by the CNR1 gene. The human CB1 receptor is expressed in the peripheral nervous system and central nervous system. It is activated by: endocannabinoids, a group of retrograde neurotransmitters that include anandamide and 2-arachidonoylglycerol (2-AG); plant phytocannabinoids, such as the compound THC which is an active constituent of the psychoactive drug cannabis; and, synthetic analogs of THC. CB1 is antagonized by the phytocannabinoid tetrahydrocannabivarin (THCV).

<span class="mw-page-title-main">Cannabinoid receptor type 2</span> Mammalian protein found in Homo sapiens

The cannabinoid receptor type 2, abbreviated as CB2, is a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the CNR2 gene. It is closely related to the cannabinoid receptor type 1 (CB1), which is largely responsible for the efficacy of endocannabinoid-mediated presynaptic-inhibition, the psychoactive properties of tetrahydrocannabinol (THC), the active agent in cannabis, and other phytocannabinoids (plant cannabinoids). The principal endogenous ligand for the CB2 receptor is 2-Arachidonoylglycerol (2-AG).

<span class="mw-page-title-main">Pravadoline</span> Chemical compound

Pravadoline (WIN 48,098) is an antinflammatory and analgesic drug with an IC50 of 4.9 μM and a Ki of 2511 nM at CB1, related in structure to nonsteroidal anti-inflammatory drugs (NSAIDs) such as indometacin. It was developed in the 1980s as a new antiinflammatory and prostaglandin synthesis inhibitor, acting through inhibition of the enzyme cyclooxygenase (COX).

<span class="mw-page-title-main">JWH-015</span> Chemical compound

JWH-015 is a chemical from the naphthoylindole family that acts as a subtype-selective cannabinoid agonist. Its affinity for CB2 receptors is 13.8 nM, while its affinity for CB1 is 383 nM, meaning that it binds almost 28 times more strongly to CB2 than to CB1. However, it still displays some CB1 activity, and in some model systems can be very potent and efficacious at activating CB1 receptors, and therefore it is not as selective as newer drugs such as JWH-133. It has been shown to possess immunomodulatory effects, and CB2 agonists may be useful in the treatment of pain and inflammation. It was discovered and named after John W. Huffman.

<span class="mw-page-title-main">JWH-200</span> Chemical compound

JWH-200 (WIN 55,225) is an analgesic chemical from the aminoalkylindole family that acts as a cannabinoid receptor agonist. Its binding affinity, Ki at the CB1 receptor is 42 nM, around the same as that of THC, but its analgesic potency in vivo was higher than that of other analogues with stronger CB1 binding affinity in vitro, around 3 times that of THC but with less sedative effect, most likely reflecting favourable pharmacokinetic characteristics. It was discovered in 1991 by Sterling Drug as a potential analgesic following the earlier identification of related compounds such as pravadoline and WIN 55,212-2.

<span class="mw-page-title-main">AM-630</span> Chemical compound

AM-630 (6-Iodopravadoline) is a drug that acts as a potent and selective inverse agonist for the cannabinoid receptor CB2, with a Ki of 32.1 nM at CB2 and 165x selectivity over CB1, at which it acted as a weak partial agonist. It is used in the study of CB2 mediated responses and has been used to investigate the possible role of CB2 receptors in the brain. AM-630 is significant as one of the first indole derived cannabinoid ligands substituted on the 6-position of the indole ring, a position that has subsequently been found to be important in determining affinity and efficacy at both the CB1 and CB2 receptors, and has led to the development of many related derivatives.

<span class="mw-page-title-main">AM-2233</span> Chemical compound

AM-2233 is a drug that acts as a highly potent full agonist for the cannabinoid receptors, with a Ki of 1.8 nM at CB1 and 2.2 nM at CB2 as the active (R) enantiomer. It was developed as a selective radioligand for the cannabinoid receptors and has been used as its 131I derivative for mapping the distribution of the CB1 receptor in the brain. AM-2233 was found to fully substitute for THC in rats, with a potency lower than that of JWH-018 but higher than WIN 55,212-2.

<span class="mw-page-title-main">SR-144,528</span> Chemical compound

SR144528 is a drug that acts as a potent and highly selective CB2 receptor inverse agonist, with a Ki of 0.6 nM at CB2 and 400 nM at the related CB1 receptor. It is used in scientific research for investigating the function of the CB2 receptor, as well as for studying the effects of CB1 receptors in isolation, as few CB1 agonists that do not also show significant activity as CB2 agonists are available. It has also been found to be an inhibitor of sterol O-acyltransferase, an effect that appears to be independent from its action on CB2 receptors.

<i>delta</i>-8-Tetrahydrocannabinol Psychoactive drug from hemp

Delta-8-tetrahydrocannabinol is a psychoactive cannabinoid found in the Cannabis plant. It is an isomer of delta-9-tetrahydrocannabinol, the compound commonly known as THC.

References

  1. ↑ "Controlled Drugs and Substance Act - Schedule II". Justice Laws Website. Government of Canada. 18 March 2021.
  2. ↑ Michalski CW, Maier M, Erkan M, Sauliunaite D, Bergmann F, Pacher P, et al. (February 2008). Gluud C (ed.). "Cannabinoids reduce markers of inflammation and fibrosis in pancreatic stellate cells". PLOS ONE. 3 (2): e1701. Bibcode:2008PLoSO...3.1701M. doi: 10.1371/journal.pone.0001701 . PMC   2253501 . PMID   18301776.
  3. ↑ Compton DR, Gold LH, Ward SJ, Balster RL, Martin BR (December 1992). "Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol". The Journal of Pharmacology and Experimental Therapeutics. 263 (3): 1118–1126. PMID   1335057.
  4. ↑ Ferraro L, Tomasini MC, Gessa GL, Bebe BW, Tanganelli S, Antonelli T (August 2001). "The cannabinoid receptor agonist WIN 55,212-2 regulates glutamate transmission in rat cerebral cortex: an in vivo and in vitro study". Cerebral Cortex. 11 (8): 728–733. doi: 10.1093/cercor/11.8.728 . PMID   11459762.
  5. ↑ Zhang Q, Ma P, Iszard M, Cole RB, Wang W, Wang G (October 2002). "In vitro metabolism of R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate, a cannabinoid receptor agonist". Drug Metabolism and Disposition. 30 (10): 1077–1086. doi:10.1124/dmd.30.10.1077. PMID   12228183. S2CID   10848076.
  6. ↑ Felder CC, Joyce KE, Briley EM, Mansouri J, Mackie K, Blond O, et al. (September 1995). "Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors". Molecular Pharmacology. 48 (3): 443–450. PMID   7565624.
  7. ↑ Meng ID, Manning BH, Martin WJ, Fields HL (September 1998). "An analgesia circuit activated by cannabinoids". Nature. 395 (6700): 381–383. Bibcode:1998Natur.395..381M. doi:10.1038/26481. PMID   9759727. S2CID   1619608.
  8. ↑ Herzberg U, Eliav E, Bennett GJ, Kopin IJ (January 1997). "The analgesic effects of R(+)-WIN 55,212-2 mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic pain". Neuroscience Letters. 221 (2–3): 157–160. doi:10.1016/S0304-3940(96)13308-5. PMID   9121688. S2CID   33643599.
  9. ↑ Bouaboula M, Poinot-Chazel C, Bourrié B, Canat X, Calandra B, Rinaldi-Carmona M, et al. (December 1995). "Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1". The Biochemical Journal. 312 ( Pt 2) (Pt 2): 637–641. doi:10.1042/bj3120637. PMC   1136308 . PMID   8526880.
  10. ↑ Morgan DJ, Muller CH, Murataeva NA, Davis BJ, Mackie K (April 2012). "Δ9-Tetrahydrocannabinol (Δ9-THC) attenuates mouse sperm motility and male fecundity". British Journal of Pharmacology. 165 (8): 2575–2583. doi:10.1111/j.1476-5381.2011.01506.x. PMC   3423255 . PMID   21615727.
  11. ↑ Kuster JE, Stevenson JI, Ward SJ, D'Ambra TE, Haycock DA (March 1993). "Aminoalkylindole binding in rat cerebellum: selective displacement by natural and synthetic cannabinoids". The Journal of Pharmacology and Experimental Therapeutics. 264 (3): 1352–1363. PMID   8450470.
  12. ↑ O'Sullivan SE (June 2016). "An update on PPAR activation by cannabinoids". British Journal of Pharmacology. 173 (12): 1899–1910. doi:10.1111/bph.13497. PMC   4882496 . PMID   27077495.
  13. ↑ Keeney BK, Meek TH, Middleton KM, Holness LF, Garland T (June 2012). "Sex differences in cannabinoid receptor-1 (CB1) pharmacology in mice selectively bred for high voluntary wheel-running behavior". Pharmacology, Biochemistry, and Behavior. 101 (4): 528–537. doi:10.1016/j.pbb.2012.02.017. PMID   22405775. S2CID   25174208.
  14. ↑ 21 U.S.C.   § 812 : Schedules of controlled substances
  15. ↑ "The Misuse of Drugs Act 1971 (Amendment) Order 2013". legislation.gov.uk.
  16. ↑ González C, Herradón E, Abalo R, Vera G, Pérez-Nievas BG, Leza JC, et al. (May 2011). "Cannabinoid/agonist WIN 55,212-2 reduces cardiac ischaemia–reperfusion injury in Zucker diabetic fatty rats: role of CB2 receptors and iNOS/eNOS". Diabetes/Metabolism Research and Reviews. 27 (4): 331–340. doi:10.1002/dmrr.1176. PMID   21309057. S2CID   32450365.
  17. ↑ Shmist YA, Goncharov I, Eichler M, Shneyvays V, Isaac A, Vogel Z, Shainberg A (February 2006). "Delta-9-tetrahydrocannabinol protects cardiac cells from hypoxia via CB2 receptor activation and nitric oxide production". Molecular and Cellular Biochemistry. 283 (1–2): 75–83. doi:10.1007/s11010-006-2346-y. PMID   16444588. S2CID   24074568.

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